This invention relates to certain novel derivatives of dopamine and to a method for the treatment of acutely depressed cardiac contractility employing such derivatives. In particular, this invention relates to 3,4-dihydroxy-N-(3-, and 4-monohydroxy-, or 3,4-dihydroxyphenylpropyl or phenylethyl)-phenethyl amines, the racemic mixtures, the optical antipodes, and the pharmaceutically acceptable acid addition salts thereof formed with mineral acids.
The clinical syndrome shock arises from a variety of causes; however, depression of the heart's contractility is frequently a contributing factor. Shock due to inadequate cardiac contractility is referred to as cardiogenic shock and is a leading cause of death. An agent for the treatment of cardiogenic shock should have a powerful inotropic effect so that it can fully reverse the cardiac contractile depression.
The sympathomimetic agents norepinephrine and isoproterenol, currently used to restore contractility in cardiogenic shock, have side effects which are life threatening.
Norepinephrine causes a vasoconstriction that can reduce blood flow to vital organs and excessively elevate aortic pressure, thereby increasing the heart's work and oxygen demand. In contrast, isoproterenol causes an excessive vasodilation in skeletal muscle diverting blood flow to that region at the expense of flow to the vital organs. Both norepinephrine and isoproterenol may induce fatal arrhythmias.
Another sympathomimetic agent, dopamine, (3,4-dihydroxyphenylethylamine) has also been used clinically for the treatment of acutely depressed cardiac contractility and shock. This drug, however, causes the release of endogenous norepinephrine and exposes the patient to life threatening cardiac arrhythmias.
Surprisingly, we have found that N substitution of dopamine or .alpha.-methyldopamine by a mono- or dihydroxyphenylalkyl group, provides compounds that are direct acting .beta.-agonists, i.e., compounds which increase cardiac contractility without releasing norepinephrine. Further, at doses that produce an equivalent increase in contractility the threat of arrhythmia is significantly less than with norepinephrine, isoproterenol or dopamine.
The cardiac stimulant amines of the present invention exert a positive inotropic effect on heart muscle without a significant increase in heart rate. At equivalent doses, the increase in heart rate is less than that produced with isoproterenol.